The Minster Practice, Lichfield

Vitamin E

Vitamin E isn't helpful and may be harmful

The antioxidant property of vitamin E has led many to use it to prevent cardiovascular or cancer related mortality. However, several studies and several previous meta-analyses have shown either no benefit or a slight increase in mortality with its use. The authors of this study (Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142: 37-46) performed a literature search an included 19 randomised studies of almost 136 000 patients, comparing vitamin E users with a control or placebo group for at least one year; trials included at least 10 deaths. In the studies the baseline death rate was approximately 10%.

Overall, there was no difference in all cause mortality between the control group and placebo group, but when low dose vitamin E was compared with high dose vitamin E (less than 400 IU/day v 400 IU/day or more), differences were found. In the studies of lower doses, there was no benefit or detriment to vitamin E supplementation (relative risk 0.98; 95% confidence interval 0.96 to 1.01). When high dose supplementation was studied separately, the risk was slightly but significantly higher in the supplemented group, with a number needed to harm of 250 (143 to 998). The effect of vitamin E supplementation was not different when the results were evaluated by patients' sex or average age, or by the length of follow up.

Conclusion: Vitamin E supplementation does not decrease all cause mortality in patients with or without pre-existing heart disease. At higher doses it can actually be harmful, although the deleterious effect is small (number needed to treat to harm = 250).

The vitamin boost that could cause early death Source: The Times Date: 11/11/2004
A new study from John Hopkins University in Baltimore, presented to the American Heart Association and published in the Annals of Internal Medicine, has found that doses of 400 international units of vitamin E, an amount usually found in a single vitamin E capsule, were associated with a 10% increased risk of death. A report in The Lancet backs up the findings, saying for every million people taking the vitamin supplements, 9,000 would die prematurely as a result. Vitamin E is a popular supplement shown to prevent blood clots and the formation of fatty plaques in the arteries. It is also credited with lowering cholesterol, combating symptoms of menopause, and reducing the risk of pre-eclampsia.

Vitamin supplements and antioxidants

Eating foods rich in antioxidants [i] [ii], such as fruit, green vegetables and wholegrain cereals has a protective effect[iii] [iv]against CHD. These dietary antioxidants, particularly vitamins C, E (a tocopherol) and b carotene (precursor of vitamin A), may protect against free radical initiated damage and LDL cholesterol oxidation[v]. It is oxidised LDL cholesterol that is thought to be involved in initial arterial injury and fibrous plaque formation[vi] [vii]. Dietary antioxidants complement the body’s enzyme antioxidants and as evidence grew that oxidative processes were linked with many distinct diseases, it was hoped that studies of dietary supplements would show benefit.

 However, there is still no conclusive evidence that supplementing the diet with antioxidant vitamins reduces risk of CHD.

The ATBC Trial[viii] did not reduce CHD mortality in male heavy smokers over 5 - 8 years follow up nor was new onset of angina reduced[ix] but the dose may have been too low. In this study, ß-carotene was associated with an increase in lung cancer and another study showed an increased mortality in male smokers with a previous MI randomised to b-carotene[x].

In another study, self administered vitamin E supplements above 100iu daily did reduce the progression of mild and moderate coronary lesions (<50% stenosis on angiography) over a 2 year period[xi]. Jha et al[xii] reviewed published epidemiological studies and randomised controlled trials involving vitamin E, vitamin C and b-carotene. Some of the case controlled studies for vitamin E showed a reduction in cardiovascular mortality but none of the randomised controlled trials showed any reduction. In summarising the evidence presented DeSilvey[xiii] concluded that patients should be told that b-carotene and vitamin C do not seem to lower cardiovascular mortality and the evidence for vitamin E is inconclusive.

Subsequent to this review, 2 randomised controlled trials were published in the New England Journal of Medicine. The first was from the Physicians Health Study[xiv]. 22,071 physicians were randomly assigned to receive beta carotene or placebo. After 12 years of supplementation, there were no significant differences, either of benefit or harm, in the overall incidence of malignant neoplasms, cardiovascular disease, stroke or overall mortality.

The Beta Carotene and Retinol Efficacy Trial (CARET)[xv] was stopped after 4 years supplementation as there may have been an adverse effect on the incidence of lung cancer (28% increase in smokers given vitamin supplements), the risk of death from lung cancer and cardiovascular disease, and death from any cause in smokers or workers exposed to asbestos. In this study, 18.341 smokers, ex-smokers and workers exposed to asbestos were given beta carotene (30mg) and retinol (25,000iu).

Low dietary vitamin C intake is associated with a high plasma fibrinogen concentration[xvi] and a higher risk of stroke.[xvii] Vitamin C lowers blood pressure[xviii] but the lower risk of stroke exceeds that expected from the magnitude of hypotensive action. Also the link between vitamin C and mortality from stroke remained after adjustment for blood pressure.[xix] 2g of vitamin C lowers serum cholesterol and prevents oxidation of LDL cholesterol [xx], and also may increase fibrinolytic activity in those with coronary heart disease.[xxi]

 The ability of blood vessels to dilate in response to normal chemical signals is an important sign of vascular health, and one that is often lost in hypertension and atherosclerosis. A study[xxii] tested the effect of vitamin C infusions on vasodilatation in 47 patients with essential hypertension and 35 matched normotensive controls. Subjects were given infusions of acetylcholine, which ordinarily causes healthy blood vessels to dilate, both with and without vitamin C infusions. In hypertensive patients, the vascular response to acetylcholine was impaired but improved with vitamin C infusion. Controls had a normal response to acetylcholine that did not change with vitamin C. In further experiments, an inhibitor of nitric oxide synthesis blocked the response to vitamin C in hypertensive patients, suggesting that the vitamin's effects are mediated through effects on nitric oxide metabolism.

 Triglycerides in fatty meals cause short term vascular dysfunction that can be prevented by pre-treatment with antioxidant vitamins C (1000mg) and E (800mg)[xxiii] [xxiv]. Whether this is associated with long term benefit is unknown.

 In two trials involving female nurses[xxv] and male health professionals[xxvi] in the US who were free of coronary heart disease on entry to the studies, use of vitamin E (100iu daily) taken long term reduced CHD risk by 30%-40%. This was after controlling for other coronary heart disease risk factors and, as a proxy for health conscious behaviour, vitamin C consumption. The benefit was not seen until after 2 years of treatment.

 A randomised double blind placebo controlled trial of vitamin E in 2002 patients with angiographically proven CHD (The Cambridge Heart Antioxidant Study[xxvii] - CHAOS) demonstrated a reduced risk of the combined primary end point of cardiovascular death plus non-fatal MI of 47% over an average follow up period of 510 days. However, within this combined end point, the benefit, which became apparent after 200 days of treatment, was from a 77% reduction in non-fatal MI. There was a small non-significant increase in risk (1.18) of cardiovascular death and most of these were in the first 200 days of treatment, so a further study designed specifically to look at mortality needs to be carried out. Another complication in the study was a dose change that was required so that recruitment would not be stopped by a shortage of study drugs. Half were treated with 800iu for 2 years and half received 400iu for 1 year. As the study was not designed to test differences between doses the results of the 2 groups were combined in the final analysis.

 The Iowa Women’s Health Study involving a prospective cohort study of postmenopausal women was used to examine a possible link between dietary antioxidants and mortality from CHD[xxviii]. 34486 postmenopausal women with no cardiovascular disease completed a questionnaire in 1986 which included details of intake of vitamins A, C and E from both dietary sources and supplements. No association with a lower CHD mortality was found for A and C. An inverse relationship between vitamin E intake and CHD mortality was shown which was more evident in the group with a high intake from dietary sources rather than supplements. The authors noted that their study was not designed to detect a benefit from higher doses of supplements over longer periods.

 The most biologically active and better retained form of vitamin E is the natural d-alpha-tocopherol. This is 49% more active than the synthetic dl-alpha-tocopherol. It is destroyed by iron[xxix] which should be taken at a different time of day. Levels are increased by OCP and absorption is enhanced by dietary fat. Anticonvulsants, such as phenytoin and carbamazepine[xxx], and also a high intake of vitamin C can reduce plasma levels, and a high intake of vitamin A reduces absorption[xxxi]. It may increase the effect of warfarin[xxxii] [xxxiii]. The safe dose range is very wide; up to 150iu is absolutely safe and up to 700iu produces minimal side effects, mainly gastrointestinal in nature. High doses have been associated with hypothyroidism. There is no carcinogenicity, mutagenicity, or teratogenicity[xxxiv].

 Other antioxidants are flavonoids; polyphenolic compounds distributed throughout plants. Several of these have been shown to have antioxidant properties in vitro, inhibiting oxidation of LDL cholesterol and inhibiting platelet aggregation. On a molecular level they modify several enzymatic actions including those involved in cell respiration and replication, drug metabolism and immune function. A Finnish study[xxxv] of a cohort of men and women aged 30-69 recruited in 1967-72 and free of heart disease at entry was followed up until 1992. Apples and onions are the main dietary sources of flavonoids and low intake of these was associated with higher risks of CHD. However, the authors noted that they could not isolate flavonoid intake from possible effects of other dietary substances or lifestyle.

 As antioxidants probably inhibit the formation of early atherosclerotic lesions, this would be their best use. Clinical trials need to be designed to concentrate on these early lesions or run for a long period. Current trials may be too short in duration to pick up a clear favourable benefit. The situation is further complicated by the fact that the mode of action is not known and optimum dose and duration of supplementation cannot therefore be calculated. Epidemiological data suggest that the dose may need to be higher to demonstrate a treatment effect in established disease, but there may be an interplay between dose and duration so improvements in diet remain the mainstay of current recommendations.

 High vitamin A intake is associated with cranial-neural birth defects[xxxvi]. The teratogenic threshold can be reached by vitamin supplements, eating liver, or fish liver oil.

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